Loading and release of water-insoluble drugs

ABSTRACT

A medical device, polymer composition, and method for delivering substantially water-insoluble drugs to tissue at desired locations within the body. At least a portion of the exterior surface of the medical device is provided with a polymer coating. Incorporated in the polymer coating is a solution of at least one substantially water-insoluble drug in a volatile organic solvent. The medical device is positioned to a desired target location within the body, whereupon the drug diffuses out of the polymer coating.

This application is a Divisional of application Ser. No. 13/483,850,filed May 30, 2012, which is a Continuation of application Ser. No.13/085,623, filed Apr. 13, 2011, which is a Division of application Ser.No. 11/833,717, filed Aug. 3, 2007, which is a Division of applicationSer. No. 11/188,850, filed Jul. 26, 2005, now abandoned, which is aContinuation of application Ser. No. 09/978,763, filed Oct. 18, 2001,now abandoned, which is a Continuation of application Ser. No.09/172,026, filed Oct. 14, 1998, now U.S. Pat. No. 6,306,166, which is aContinuation-in-part of application Ser. No. 09/133,603, filed Aug. 13,1998, now abandoned, which is a Continuation-in-part of application Ser.No. 08/910,136, filed Aug. 13, 1997, now abandoned, the contents of eachof which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention relates to methods and devices for the localized deliveryof substantially water-insoluble drug agents within the body.

BACKGROUND

The systemic administration of drug agents, such as by transoral orintravenous means, treats the body as a whole even though the disease tobe treated may be localized. In such a case, systemic administration maynot be desirable because, for example, the drug agents may have unwantedeffects on parts of the body which are not to be treated, or becausetreatment of the diseased part of the body requires a high concentrationof drug agent that may not be achievable by systemic administration.

It is therefore often desirable to administer drug agents at a localizedsite within the body. Common examples include cases of localized diseaseor occluded body lumens. Various methods have been proposed for suchlocalized drug administration. For example, U.S. Pat. No. 5,304,121,hereby incorporated by reference, discloses a method of deliveringwater-soluble drugs to tissue at desired locations of a body lumen wall.The method generally includes the steps of impregnating a hydrogelpolymer on an expandable catheter with an aqueous drug solution,inserting the catheter into a blood vessel to a desired location, andexpanding the catheter against the surrounding tissue allowing therelease of the drug to the tissue. This method of localized drugdelivery using hydrogel polymer impregnation has a limitation of beingapplicable to drug agents which are dissolved in water at concentrationssufficient for therapeutic gel loading levels. There thus exists a needfor a method and apparatus for the localized delivery of drug agentswithin the body, where the drug agents are substantiallywater-insoluble. Moreover, there exists a need for a method andimplantable device that provides a sustained release of suchsubstantially water-insoluble drug agents over a time frame effective toinhibit proliferative disease.

SUMMARY OF THE INVENTION

One objective of the present invention is to provide a method andapparatus for the localized delivery of substantially water-insolubledrug agents to predetermined locations within the human body.

A further objective of the present invention is to provide a method andapparatus to facilitate gradual, localized release of drug agents atpredetermined locations within the human body.

A further objective of the invention is to administer drug agents bydiffusion directly into the tissue requiring treatment. The drug ispreferably applied in a manner that does not further injure the tissueto be treated, and administration is selectively and evenly distributedover the treated area such that the drug can be taken up by the tissue,without, for example, being washed away by body fluids.

The present invention provides methods and medical devices for thelocalized delivery of substantially water-insoluble drugs agents.

A particular embodiment of the present invention features a catheter andmethod for delivering substantially water-insoluble drug agents totissue at a desired location along body lumen walls. The catheter isconstructed for insertion in a body lumen and has a catheter shaft andan expandable portion mounted on the catheter shaft. The expandableportion is expandable to fill the cross-section of the body lumen. Atleast a portion of the exterior surface of the expandable portion isdefined by a polymer coating. Incorporated into the polymer coating isat least one substantially water-insoluble drug. The catheter ispositioned to a desired target location within the body, whereupon thepolymer coating absorbs water, thus dissolving the drug and resulting inthe diffusion of the drug out of the polymer coating. The polymer anddrug are selected to allow controlled release of a desired dosage of thedrug from the polymer.

Another particular embodiment of the present invention features a stentfor the localized delivery of substantially water-insoluble drug agentsto tissue at a desired location along body lumen walls. The stent is atleast partially coated with a polymer coating having at least onesubstantially water-insoluble drug therein. The stent configuration,polymer and drug are selected to allow for the controlled release dosageand release rate of the drug from the polymer.

In a most preferred embodiment, the stent is a patterned stent for thelocalized delivery of paclitaxel to tissue at a desired location alongbody lumen walls. The stent is at least partially coated with apolymer/paclitaxel matrix that provides sustained release of paclitaxelat the desired site within the lumen wall.

In another aspect of the invention, there is provided a method forpreventing or inhibiting proliferative disease in a patient comprisingimplanting a patterned stent comprising an outer coating ofpolymer/paclitaxel at a site of cellular proliferation, wherein thepaclitaxel is released from the outer coating at a release rate and fora period of time sufficient to inhibit or prevent cellular proliferationat the site.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1A shows one embodiment of the present invention in which a drugsolution is impregnated into a polymer-coated balloon catheter.

FIG. 1B shows the insertion of a polymer-coated balloon catheter into abody lumen, in accordance with the present invention.

FIG. 1C shows the expansion of a polymer-coated balloon catheter at anocclusion site within a body lumen, in accordance with the presentinvention.

FIG. 2A shows a drug delivery balloon catheter embodiment of the presentinvention including a sheath for covering the catheter as it is beingmoved through a vessel toward the occlusion to be treated.

FIG. 2B shows a drug delivery balloon catheter embodiment of the presentinvention at an occlusion site within a body lumen, in accordance withthe present invention.

FIGS. 3A and 3B show the release profile of paclitaxel from a ballooncatheter having a polyacrylic acid-based coating for up to 50 and 5000minutes, respectively, in accordance with the present invention.

FIGS. 4A and 4B show the release profile of dexamethasone from a ballooncatheter having a polyacrylic acid-based coating for up to 30 and 400minutes, respectively, in accordance with the present invention.

FIG. 5 shows the release profiles of molsidomine from various ballooncatheters having a polyacrylic acid-based coating for up to 5 minutes,in accordance with the present invention.

FIG. 6 shows the release profiles of dexamethasone from various ballooncatheters having a polyacrylic acid-based coating for up to 450 minutes,in accordance with the present invention.

FIGS. 7A and 7B show the release profiles of water-soluble andsubstantially water-insoluble estradiol from balloon catheters having apolyacrylic acid-based coatings for up to 10 and 200 minutes,respectively, in accordance with the present invention.

FIG. 8 shows the release profile of paclitaxel for up to 10 days frompolyurethane coated stents dipped in 30 mg/ml paclitaxel in ethanol for3 days, in accordance with the present invention.

FIG. 9 shows the release profiles of paclitaxel from variouspolyurethane-coated balloon catheters for up to 2 hours, in accordancewith the present invention.

FIG. 10 shows the cumulative release profile of paclitaxel over a timeframe of days. This figure shows the cumulative release of paclitaxelfor delivery rates of 5 μg/day and 0.5 μg/day.

DETAILED DESCRIPTION

The present invention provides methods and medical devices for thelocalized delivery of one or more substantially water-insoluble drugagents to predetermined locations within the human body, such as withinthe vascular system, urinary tract, prostate, esophagus, colon, brain,etc.

In accordance with an embodiment of the invention, a substantiallywater-insoluble drug agent is dissolved in a volatile organic solvent.“Organic solvent” is intended to mean a singular organic solvent or asolvent mixture having at least one organic component. The solventmixture also includes mixtures of water with miscible organic solvents.The drug solution is then applied to a polymer coating on a medicaldevice that is adapted for insertion into the body. Examples of suchmedical devices include catheters, guide wires, balloons, filters (e.g.,vena cava filters), stents, stent grafts, vascular grafts, intraluminalpaving systems, implants and other devices used in connection withdrug-loaded polymer coatings. Such devices are implanted or otherwiseutilized in body lumina and organs such as the coronary vasculature,esophagus, trachea, colon, biliary tract, urinary tract, prostate,brain, and the like. Examples of suitable vascular grafts are describedin U.S. Pat. Nos. 5,509,931, 5,527,353, and 5,556,426. Vena cava filterssuch as those described in WO 96/12448 and WO 96/17634 may also be usedin the present invention. All of foregoing documents identified bynumber are incorporated herein in their entireties.

The filters that can be provided with a polymeric material/drug-agentmatrix in accordance with the present invention include, for example,thrombus filters that can be placed at a selected location within thevascular system and removed when no longer required. A preferredlocation for placement of these filters is the vena cava. Filters placedin the vascular system can intercept blood clots that may otherwisetravel to the lungs and result in a pulmonary embolism, alife-threatening emergency that has become increasingly common. In oneembodiment of the present invention there is provided such an implantedvascular filter having a polymeric material/drug outer coating thereon.In a most preferred embodiment, the filter has a polymericmaterial/paclitaxel outer coating, and most preferably, a polylacticacid/polycaprolactone copolymer/paclitaxel coating. The polymericcoating may also have incorporated therein or thereon any othertherapeutic agent that is used for reducing the formation of, orcomplications due to, clot formation or neointima formation. Suchagents, include, but are not limited to antithrombogenic agents andthrombolytic agents and other antiproliferative agents.

Further examples of filters that may be provided with the polymericmaterial/drug coating in accordance with present invention include,e.g., those described in International Application No. WO 96/17634 andInternational Application No. WO 96/12448, both of which are hereinincorporated by reference.

The grafts, including stent grafts, that can be provided with apolymeric material/drug agent matrix in accordance with the presentinvention include synthetic vascular grafts that can be used forreplacement of blood vessels in part or in whole. A typical vasculargraft is a synthetic tube with each end thereof sutured to the remainingends of a blood vessel from which a diseased or otherwise damagedportion has been removed. In a typical stent graft, each end of thesynthetic tube portion includes a stent that is affixed to each of theremaining ends of a blood vessel from which a diseased or otherwisedamaged portion has been removed. Alternatively, in a stent graft, thereplacement vessel may be segment of a vessel removed from anotherlocation in the patient, such as a portion of a femoral artery or thelike. In the case of a synthetic graft, the graft is typically tubularand may be, e.g., of a woven, knit or velour construction. Preferredmaterials for the grafts and covering material for the stent graftsinclude polyethylene terephthalate and polytetrafluoroethylene. Thevascular grafts may be reinforced with, for example, helices, rings,etc. in order to provide uniform strength over the entire surface of thegraft tubing. The materials of which such grafts are constructed arebiologically compatible materials including, but not limited to,thermoplastic materials such as polyester, polytetrafluoroethylene(PTFE), silicone and polyurethanes. The preferred materials includepolyester fibers and PTFE.

Examples of other suitable grafts are described in U.S. Pat. Nos.5,509,931, 5,527,353, and 5,556,426, all of which are hereinincorporated by reference. In a most preferred embodiment of theinvention, the graft is provided with a coating of polymericmaterial/paclitaxel, and most preferably, the polymeric material is acopolymer of polycaprolactone and polylactic acid. Thispaclitaxel-coated graft, when positioned at a desired site in the bodyprovides an extended release of paclitaxel to the site.

A polymeric material/drug agent matrix in accordance with the presentinvention may be used as an intraluminal paving system. In suchintraluminal paving systems as are known in the art, the polymericmaterial/drug agent matrix will typically be applied directly to aninterior surface of vascular or non-vascular lumina. An intraluminalpaving system is formed, for example, by admixing a drug agent with aliquid polymer, in the absence of a solvent, to form a liquidpolymer/drug agent mixture. The mixture is then applied directly to aluminal surface by any conventional method, such as by injecting themixture against the luminal surface. Curing of the mixture typicallyoccurs in-situ. To facilitate curing, a cross-linking or curing agentmay be added to the mixture prior to application thereof to the luminalsurface. Addition of the cross-linking or curing agent to thepolymer/drug agent liquid mixture must not occur too far in advance ofthe application of the mixture to the luminal surface in order to avoidover-curing of the mixture prior to application thereof to the luminalsurface. Curing may also occur in-situ by exposing the polymer/drugagent mixture, after application to the luminal surface, to radiationsuch as ultraviolet radiation or laser light, heat, or by contact withmetabolic fluids such as water at the site where the mixture has beenapplied to the luminal surface. In a preferred intraluminal pavingsystem in accordance with the invention, the drug agent is paclitaxeland the paclitaxel may be incorporated in the polymeric material aloneor in combination with another drug agent. In intraluminal pavingsystems in accordance with a preferred embodiment of the presentinvention, the polymeric material incorporating the paclitaxel and, ifdesired, any additional therapeutic agent(s), may be eitherbioabsorbable or biostable. Any of the polymers described herein thatmay be formulated as a liquid may be used to form the polymer/drug agentmixture for use as an intraluminal paving system.

In a preferred embodiment, the polymer used to coat the medical deviceis provided in the form of a coating on an expandable portion of amedical device. After applying the drug solution to the polymer andevaporating the volatile solvent from the polymer, the medical device isinserted into a body lumen where it is positioned to a target location.In the case of a balloon catheter, the expandable portion of thecatheter is subsequently expanded to bring the drug-impregnated polymercoating into contact with the lumen wall. The drug is released from thepolymer as it slowly dissolves into the aqueous bodily fluids anddiffuses out of the polymer. This enables administration of the drug tobe site-specific, limiting the exposure of the rest of the body to thedrug.

The polymer used in the present invention is preferably capable ofabsorbing a substantial amount of drug solution. When applied as acoating on a medical device in accordance with the present invention,the dry polymer is typically on the order of from about 1 to about 50microns thick. In the case of a balloon catheter, the thickness ispreferably about 1 to 10 microns thick, and more preferably about 2 to 5microns. Very thin polymer coatings, e.g., of about 0.2-0.3 microns andmuch thicker coatings, e.g., more than 10 microns, are also possible. Itis also within the scope of the present invention to apply multiplelayers of polymer coating onto a medical device. Such multiple layersare of the same or different polymer materials.

The polymer of the present invention is hydrophilic or hydrophobic, andis selected from the group consisting of polycarboxylic acids,cellulosic polymers, including cellulose acetate and cellulose nitrate,gelatin, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone,polyanhydrides including maleic anhydride polymers, polyamides,polyvinyl alcohols, copolymers of vinyl monomers such as EVA, polyvinylethers, polyvinyl aromatics, polyethylene oxides, glycosaminoglycans,polysaccharides, polyesters including polyethylene terephthalate,polyacrylamides, polyethers, polyether sulfone, polycarbonate,polyalkylenes including polypropylene, polyethylene and high molecularweight polyethylene, halogenated polyalkylenes includingpolytetrafluoroethylene, polyurethanes, polyorthoesters, proteins,polypeptides, silicones, siloxane polymers, polylactic acid,polyglycolic acid, polycaprolactone, polyhydroxybutyrate valerate andblends and copolymers thereof as well as other biodegradable,bioabsorbable and biostable polymers and copolymers. Coatings frompolymer dispersions such as polyurethane dispersions (BAYHDROL®, etc.)and acrylic latex dispersions are also within the scope of the presentinvention. The polymer may be a protein polymer, fibrin, collage andderivatives thereof, polysaccharides such as celluloses, starches,dextrans, alginates and derivatives of these polysaccharides, anextracellular matrix component, hyaluronic acid, or another biologicagent or a suitable mixture of any of these, for example. In oneembodiment of the invention, the preferred polymer is polyacrylic acid,available as HYDROPLUS® (Boston Scientific Corporation, Natick, Mass.),and described in U.S. Pat. No. 5,091,205, the disclosure of which ishereby incorporated herein by reference. U.S. Pat. No. 5,091,205describes medical devices coated with one or more polyisocyanates suchthat the devices become instantly lubricious when exposed to bodyfluids. In a most preferred embodiment of the invention, the polymer isa copolymer of polylactic acid and polycaprolactone.

By “substantially water-insoluble drug” is meant any therapeutic agenthaving a greater solubility in organics than in water. Morespecifically, such drugs have a water solubility of no greater than 1part drug to 30 parts water, more typically no greater than 1 part drugto 1,000 parts water. Such solubilities are described as “sparinglysoluble” to “very slightly soluble” in the art.

The drug agents used in the present invention are selected from a numberof drug types depending on the desired application. For example, thesedrugs include anti-inflammatory agents such as dexamethasone,prednisolone, corticosterone, budesonide, estrogen, sulfasalazine,mesalamine, and analogues thereof;antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel,5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones,endostatin, angiostatin, thymidine kinase inhibitors, and analoguesthereof; anesthetic agents such as lidocaine, bupivacaine, ropivacaine,and analogues thereof; anti-coagulants; and growth factors.

The drug agents useful in accordance with the present invention may beused singly or in combination. For example, an anti-proliferative agentsuch as paclitaxel may be used in combination with another drug agent,such as an anticoagulant, anti-inflammatory, antithrombogenic,thrombolytic, nitric oxide-containing polymer, or a vascular cellpromoter such as VEGF, for example.

Paclitaxel is a preferred drug agent for use in accordance with thepresent invention either alone or in combination with another drugagent, as described above. Paclitaxel is a complex alkaloid extractedfrom the Pacific Yew Taxusbrevifolia Family (Family Taxacea) which hasbeen demonstrated to have antiproliferative activity. As used herein,paclitaxel includes the alkaloid and any pharmacologically activederivative or analog thereof. Thus paclitaxel includes naturallyoccurring forms and derivatives thereof and synthetic and semi-syntheticforms thereof. TAXOL® is a commercially available form of paclitaxel.

In accordance with the present invention, the drug agents are dissolvedin a volatile organic solvent such as, for example, ethanol,isopropanol, chloroform, acetone, pentane, hexane, or methylenechloride, to produce a drug solution. In the case of paclitaxel thepreferred solvent is chloroform. The drug solution is then applied tothe polymer. A volatile organic solvent typically is selected to providedrug solubilities much greater than the corresponding aqueous solubilityfor the substantially water-insoluble drug. Accordingly, application ofthe drug solution to the polymer often results in drug loadings that areorders of magnitude greater than loadings that can be achieved byapplication of a saturated aqueous solution of the drug to the polymer.

The drug solution is applied to the polymer coating by any suitablemeans, including dipping the polymer coating into the drug solution orby applying the solution onto the coating such as by pipet or byspraying, for example. In the former method, the amount of drug loadingis controlled by regulating the time the polymer is immersed in the drugsolution, the extent of polymer cross-linking, the concentration of thedrug in the solution and/or the amount of polymer coating. In anotherembodiment of the invention, the drug is incorporated directly into thepolymer prior to the application of the polymer topcoat as a coatingonto a medical device.

After applying the drug solution to the polymer coating, the volatilesolvent is evaporated from the coating, for example, by drying in air orin an oven.

The release profile of the drug from the polymer coating is determinedby many factors including the drug solubility, amount of drug appliedand the thickness and porosity of the polymer coating.

In a preferred embodiment of the present invention, one or moreadditional layers may be applied over at least a portion of a medicaldevice previously coated with a polymer/drug agent in accordance withthe present invention. Desirably, such an additional layer will beprovided to modify or modulate the release of one or more of the drugagents in the underlying layer. For example, a polymeric coating may beapplied over the previously applied polymer/drug agent coating tomodulate the release rate of the drug agent in that layer. Thisadditional release rate-modifying or modulating layer may be applied ina subsequent coating step in a manner similar to that disclosed herein,for example by spraying a polymer solution onto the previously appliedcoating layer or by dipping the previously coated medical device into asolution of the polymer selected to form the modifying or modulatinglayer. However, other methods for applying polymeric materials tosubstrates, including, for example, in-situ polymerization methods suchas plasma polymerization may also be used to provide the additionalrelease rate-modifying or modulating polymeric layer. Such otherapplication processes included within the scope of the present inventionare those that will not detrimentally affect the previously appliedlayer, including the drug agent(s) incorporated therein or thereon. Theadditional layer may also include one or more additional drug agentsincluding any of the drug agents incorporated into the underlyingpolymer/drug agent coating layer. Prior to application of the modifyingor modulating layer, any conventional adhesion promotion agent may beapplied to the previously applied coating, or other treatment thereofmay be conducted, in order to promote adhesion of the modifying ormodulating layer to the previously applied coating. Where the modifyingor modulating layer is applied in a manner similar to the underlyinglayer, the polymeric material used for the modifying or modulating layercan be any of the polymers described herein. Where such polymericmaterial is applied, for example, by plasma polymerization, the polymersare those that can be formed by monomers in a gas phase that can beactivated for example by radio frequency waves. Such monomers include,for example, silicone-based monomers such as cyclic or acyclicsiloxanes, silanes, silylimidazoles; fluorine-based monomers such ashydrofluorocarbons; aliphatic or aromatic hydrocarbons; acrylicmonomers; and combinations thereof. The monomer gas may have functionalgroups that facilitate later attachment of drug agents thereto bycovalent bonding, for example. Any appropriate polymer for the modifyingor modulating layer is preferably selected to have a porosity thatprovides the modifying or modulating effect as described above. Theporosity of this polymeric material may also be modified by addition ofporosigens or other porosity-effecting adjuvants that are conventionallyadded to polymers for this purpose. Other factors guiding the selectionof a modulating or modifying polymer include, but are not limited to,the thickness of coating layer, the tortuosity of the polymeric materialaffecting the path of resistance to drug mobility within the polymericmaterial, the cross-linking density, drug solubility in the modulatingor modifying layer, etc. The thickness of the modifying or modulatinglayer will preferably be less than 5,000

, and more preferably in the range of from about 50-2000

. A preferred modifying or modulating polymer in accordance with thepresent invention is a siloxane polymer formed, for example, by a plasmapolymerization process. This siloxane modifying or modulating polymer ispreferably applied to a medical device that has a polyurethane/drugagent coating previously applied thereto in accordance with the presentinvention.

When an expandable member such as a balloon catheter is used toadminister the drug, pressure can be used to increase the rate of drugtransfer to the tissue. An increase in pressure increases the diameterof the balloon and therefore the diameter of the surrounding tissue,thereby increasing the surface area for drug transfer. The amount ofdrug that is delivered per unit time is therefore increased.

When an expandable catheter is chosen as the medical device of thepresent invention, the expandable portion is preferably a balloon, inwhich case the drug is placed in the polymer for controlled release ofthe drug upon expansion of the balloon against a body lumen. Theexpandable portion optionally includes a stent, mountable in a bodylumen by expansion thereof. The catheter also optionally comprises asheath member which is extendable over the expandable portion to inhibitrelease of the drug into body fluids during placement of the catheter.

Referring now to FIGS. 1A-1C, an embodiment for the localized deliveryof substantially water-insoluble drugs to a predetermined locationwithin the body is described. The drug administration method shown inFIGS. 1A-1C illustrates the use of the present invention in conjunctionwith an angioplasty process. Catheter device 1 comprises a body 3 havinga balloon 4 attached at its distal end. The balloon 4 on the catheter 3includes a polymer coating 6. As shown in FIG. 1A, drug solution 8 isimpregnated into the polymer coating with the balloon in itssubstantially deflated state prior to insertion into the patient. Asshown in FIG. 1B, after the volatile solvent is evaporated, the device 1is inserted into a body lumen 2 having a region to be treated, such asan occlusion due to a deposition of plaque 5 on the lumen wall tissue 9.The device 1 is moved along the vessel to position the balloon 4 at theocclusion site, as shown in FIG. 1C. The lumen may be, for example, anarrow, tortuous opening through which the catheter is passed bytorquing or other known techniques. As shown in FIG. 1C, the balloon isinflated to provide close contact between the drug-impregnated polymercoating 6 and the surrounding plaque and tissue. As water from the bodypenetrates into the polymer coating 6, it begins to dissolve the drugagent, which subsequently diffuses out of the polymer coating 6 and intothe surrounding plaque and tissue.

During drug administration, a substantial amount of the drug containedin the polymer coating is diffused into the affected area. The inflationpressure needed to expand the balloon catheter and dilate the lumen, ifnecessary, is typically in the range of about 1 to 20 atm. The balloonis formed of any suitable materials such as vinyl polymers such aspolyethylene; polyesters such as polyethylene terephthalate; polyamidessuch as nylon; polyolefins and copolymers thereof (e.g., Selar, Pebax,Surlyn, Hytrel, etc.). The balloon is optionally a perfusion balloon,which allows blood to perfuse the catheter to prevent ischemia duringdelivery. A perfusion balloon is particularly preferred for longarterial delivery times and when the delivery drug is only very slightlysoluble in water.

Referring to the embodiment of the invention illustrated in FIGS. 2A and2B, the balloon portion 4 of catheter 3 is optionally covered by aprotective sheath 7 while the instrument 1 is inserted into a body lumen2 and positioned at a treatment region. As the coated balloon 4 ispositioned at occluded site 5, as shown in FIG. 2B, the protectivesheath 7 is drawn back to expose the balloon 4. In an alternativeembodiment, the sheath remains stationary while the catheter moves thecoated balloon forward into the occluded region. The sheath 7 protectsthe coating and inhibits premature release of the drug. Such a sheathmight be particularly advantageous when using drugs which are notsufficiently water-insoluble or if even minor delivery to tissue duringcatheter placement is a problem, e.g. for extremely toxic drugs.

Although FIGS. 1A-1C and 2A-2B illustrate the application of the presentinvention to an angioplasty process, the present invention is also usedto administer drug agents to target locations where there is noocclusive formation.

In other embodiments, the medical device of the present invention is animplantable medical device such as a stent, covered stent, stent graft,intraluminal paving system, wire guide, cannulae, artificial limbs,joints, and other prosthetic devices. Where a stent is used it mayeither balloon- or self-expandable, and is constructed of anybiocompatible material. The grafts and covering materials for the stentgrafts are made of any biocompatible material such as, for example,polyurethane, polyesters, silicone, or polytetrafluoroethylene.

Stents are generally configured in one of two configurations: patternedor coil. Coil-type stents include, for example, wire stents in the formof coils, spirals or the like, with or without spines, an example ofwhich is the subject of U.S. Pat. No. 4,886,062 (incorporated herein byreference), another example of which is the GR-II® (Cook Inc.) stent.Patterned stents used in accordance with a most preferred embodiment ofthe invention include all stents other than coil-type stents such as,for example, slotted tube stents, criss-cross tubular stents, braidedstents, hexagonal stents, nets, articulated stents, and the like.Patterned stents are also generally preferred over coil stents becausethey provide more radial support for surrounding body lumina. Preferredpatterned stents for use in the present invention include the NIR™ andRADIUS™ stents (SCIMED Life Systems, Inc.) as described in U.S. Pat. No.5,733,303 and WO 96/26689 (both of which are incorporated herein byreference); the WALLSTENT® (Schneider Inc.) as described in U.S. Pat.Nos. 4,655,771 and 5,061,275 (both of which are incorporated herein byreference); and the SYMPHONY® stent (Boston Scientific Corp.) asdescribed in U.S. Pat. No. 5,540,712 (incorporated herein by reference).The stents and stent grafts described in U.S. Pat. Nos. 5,766,237,5,681,356, 5,522,881 and 5,776,180 (each of which is incorporated hereinby reference) and the polymer stents described in U.S. Pat. No.5,769,883 (incorporated herein by reference) are also within the scopeof the present invention.

The implantation of a stent, stent graft, vascular graft or filter inaccordance with the present invention can be conducted by any medicalprocedure conventionally used for such implantation. In the case of astent, a polymer/paclitaxel coated stent in accordance with the presentinvention can be fitted over the inflatable element of a ballooncatheter and expanded by the balloon to force the stent into contactwith the body lumen at or near a site of injury such as, for example,within an injured blood vessel.

Where the medical device in accordance with the present invention is,e.g., a catheter, stent, graft, filter, etc., or any other device usedin the vascular system, any blood vessel including arteries, veins andcapillaries may be treated in accordance with the present invention.These blood vessels may be in or near any organ in the human ormammalian body.

In a most preferred embodiment of the invention, a patterned stenthaving a polymer/paclitaxel coating is used to prevent or inhibitproliferative disease.

As used herein, “proliferative disease” means any disease or disorderincluding cancers, malignancies, benign growths and other conditionsthat result from hyperactivity or hyperplasia of somatic cells, andincludes restenosis and vascular hyperplasia such as neointimalhyperplasia. Such proliferative diseases may occur in vascular and otherluminal or non-luminal regions of the body.

The inventors have surprisingly found that extended drug release ofpaclitaxel from a polymer coating on a patterned stent is obtained andconsequently, a significant reduction in neointima formation results.The reduction in neointima formation obtained with patterned stents usedin accordance with the present invention is surprisingly superior tothat obtained using a coiled stent coated with a polymer/paclitaxelmatrix. FIG. 10 shows the release rate of paclitaxel obtained with astent in accordance with the present invention. In a preferredembodiment, paclitaxel is released from a polymer/paclitaxel coatedstent for a time period of at least about 28 days after implantation ofstent at the desired location within the body. The patterned stent iscoated with an outer coating of polymer/paclitaxel such that the amountof paclitaxel is sufficient to prevent, decrease, eliminate or modifycellular proliferation associated with proliferative disease ordisorder. The amount of paclitaxel sufficient to inhibit or preventproliferative disease will vary according to the size of the patternedstents, but is generally in the range of from about 50 μg to 500 μg perstent.

Procedures for preparing a drug delivery medical device with a polymercoating are presented in the following non-limiting examples.

Example 1 Release Kinetics of Paclitaxel from Polyacrylic Acid-BasedCoating

A 2 mg/ml solution of paclitaxel is prepared in chloroform. The solutionis gently agitated until the paclitaxel is completely dissolved. Thesolution is applied via pipet to a balloon catheter having a polyacrylicacid-based coating and inflated to 2 atm. A total of 100 μl of solution,and hence 200 μg of paclitaxel, is applied to the catheter. The ballooncatheter is then dried in air for 30 minutes and in a vacuum oven for 48hours at 50° C. to evaporate the chloroform. The catheter is thenimmersed in a solution of 1% dimethyl sulfoxide (DMSO) and phosphatebuffered saline (PBS) having a pH of 7.4 for in-vitro drug release. Thecumulative amount of paclitaxel released from the catheter coatingyields the data shown in FIGS. 3A and 3B.

Example 2 Release Kinetics of Dexamethasone from Polyacrylic Acid-BasedCoating

Solutions containing 1.5 mg/ml and 200 μg/ml of dexamethasone inchloroform, are prepared by gently agitating until the dexamethasone iscompletely dissolved. The solutions are separately applied via drippingto separate balloon catheters having polyacrylic acid-based coatings andinflated to 2 atm. A total of 100 μl of each solution is applied to eachrespective catheter, corresponding to dexamethasone loadings of 1.5 mgand 200 μg, respectively. These results can be contrasted with theinability to apply substantial amounts of dexamethasone to polyacrylicacid-based coatings using aqueous solutions, in which case only about 1μg of dexamethasone can be loaded into such coatings. The ballooncatheters are then dried in a vacuum oven for 2 hours at 50° C. toevaporate the chloroform solvent. The catheters are thereafter immersedin PBS (pH=7.4) to track the release of dexamethasone over time. Thecumulative amount of dexamethasone released from each catheter yieldsthe data shown in FIGS. 4A and 4B.

Example 3 Release Kinetic of Molsidomine from Polyacrylic Acid-BasedCoating

Various solutions of molsidomine in volatile solvents are prepared andapplied to balloon catheters by the methods indicated in Table I. In the“dip” application technique, each balloon catheter having a polyacrylicacid-based coating is dipped into its respective solution for 10minutes. In the “pipet” application technique, 200 μl of solution ispipetted onto its respective coated balloon catheter while slowlyturning. All samples are dried in an oven for 30 minutes at 50° C. andthereafter immersed in PBS (pH=7.4) to track the release of molsidomineover time. The cumulative amount of molsidomine released from eachcatheter yields the data shown in FIGS. 5A and 5B.

TABLE I Molsidomine solution characterization, and methods of applyingmolsidomine solution to polymer coated catheters. Concentration (mgMolsidomine per ml Application Sample Solvent solvent) technique 1chloroform 150 dip 2 chloroform 30 pipet 3 chloroform 150 pipet 4ethanol 30 pipet 5 ethanol 30 dip

Example 4 Release Kinetics of Dexamethasone Added to PolyacrylicAcid-Based Topcoat Formulation

Rather than forming a solution of dexamethasone in an organic solventand then applying this solution to polymer-coated balloon catheters asin Example 2, dexamethasone is added directly to the polymer used tocoat the balloon catheters. Dexamethasone is weighed out into 0.05 g,0.1 g, and 0.2 g samples, each of which is each added to 1 ml lots ofpolymer topcoat solution containing polyacrylic acid, methyl ethylketone, dimethyl formamide, and t-butyl alcohol. The dexamethasonesamples are mixed with the polymer topcoat solutions until completelydissolved. The dexamethasone-containing polymer topcoat solutions areseparately applied via dripping to separate, uncoated balloon cathetersinflated to 2 atm. After drying in a vacuum oven for 2 hours at 50° C.,the catheters are immersed in PBS (pH=7.4) to track the release ofdexamethasone over time. The cumulative amount of dexamethasone releasedfrom each catheter yields the data shown in FIG. 6.

Example 5 Comparative Release Kinetics for Water-Soluble andWater-Insoluble Estradiol

Estradiol is provided in both water-soluble and substantiallywater-insoluble forms. Water-soluble estradiol is applied to a ballooncatheter coated with a polyacrylic acid-based coating by i) preparing a10 mg/ml solution of water-soluble estradiol in deionized,ultra-filtered water; and ii) placing the balloon catheter, inflated to2 atm, into 200 μl of the solution for 20 minutes. Water-insolubleestradiol is applied to a balloon catheter coated with apolyacrylic-acid based coating by i) preparing a 10 mg/ml solution ofsubstantially water-insoluble estradiol in methanol; and ii) dripping100 μl of the solution onto the balloon catheter. The catheters arethereafter immersed in PBS (pH=7.4) to track the release of bothwater-soluble and water-insoluble estradiol over time. Greater releaseis observed for the substantially water-insoluble form of estradiol whencompared to the water-soluble form. The cumulative amount of estradiolreleased from each catheter yields the data shown in FIGS. 7A and 7B.

Example 6 In-Vivo Delivery of Paclitaxel from Polyacrylic Acid-BasedCoating

A 9.8 mg/ml solution of radio-labeled paclitaxel in chloroform isprepared. A total of 50 μl of the solution is applied via pipet to aballoon catheter having a polyacrylic acid-based coating. The paclitaxelfrom the coated balloon catheter is then released in-vivo to porcinearteries. After release for a predetermined amount of time, thepaclitaxel remaining in the coating is extracted using two sequentialethanol washes. The amount of paclitaxel released in the pigbloodstream, as calculated from the amount of paclitaxel loaded into thecoating minus that extracted from the coating after delivery, is shownin Table II.

TABLE II Amount of paclitaxel released into pig bloodstream from animpregnated, polyacrylic acid-based coated balloon catheter, as afunction of delivery time. Amount of Amount of paclitaxel paclitaxel %of Amount of extracted from released in paclitaxel time in balloon afterbloodstream released in bloodstream delivery (μg) (μg) bloodstream 1minute 182 ± 1  307 63 5 minutes 160 ± 30 330 68

Example 7 Delivery of Paclitaxel to Explanted Porcine Arteries fromPolyacrylic Acid-Based Coating

A 9.8 mg/ml solution of radio-labeled paclitaxel in chloroform isprepared. A total of 50 μl of the solution is applied via pipet to aballoon catheter having a polyacrylic acid-based coating. The coatedballoon catheter is then delivered to an explanted porcine artery for 15minutes. After delivery, the paclitaxel remaining in the coating isextracted using two sequential ethanol washes. The delivered paclitaxelis extracted from the vessel, also by using two sequential ethanolwashes. In addition, the vessel is placed in tissue solvent and countedfor paclitaxel. Using these extraction methods, at least 80% of thepaclitaxel loaded onto the balloon catheter is recovered, as shown inTable III.

TABLE III Paclitaxel recovery from ex vivo delivery to porcine artery.Amount paclitaxel loaded onto balloon 489 μg Amount paclitaxel extractedfrom the 360 μg balloon after delivery Amount paclitaxel extracted fromartery  30 μg Amount paclitaxel counted from tissue  1 μg solution Totalpaclitaxel measured 391 μg Percentage of paclitaxel recovered 80%

Example 8 Release Kinetics of Paclitaxel from Polyurethane-Based StentCoating

Slotted tube stainless steel stents are coated with polyurethane byspraying a 1 wt % solution of CHRONOFLEX® polyurethane (made by CTBiomaterials) in tetrahydrofuran directly onto the stent surface. Thecoated stents are dried in a vacuum oven for three hours at 70° C.

Each polyurethane coated stent is placed in a vial, which is filled tomaximum volume (1.5 ml) with a solution of paclitaxel in ethanol, andsealed. The stent is stored in the vial for three days at roomtemperature. The stent is then removed from the vial and dried for onehour at 65° C.

The above procedure is conducted using solutions of varyingconcentrations. Each stent is analyzed for paclitaxel content byextraction in dichloromethane solvent. The results are presented inTable IV below. Samples 1 and 2 were obtained using a paclitaxelconcentration of 10 mg/ml, samples 3 and 4 using a 20 mg/ml solution andsample 5 and 6 using a 30 mg/ml solution.

TABLE IV Paclitaxel content. μg Paclitaxel Paclitaxel Coating Paclitaxelconc. content Wt. per Sample # (mg/ml) (μg) (μg) μg coating 1 10 44.8796 0.06 2 10 88.2 859 0.10 3 20 151.2 718 0.21 4 20 127.6 702 0.18 5 30157.1 736 0.21 6 30 144.3 629 0.23

These results suggest that paclitaxel loading is relatively independentof paclitaxel concentration above 20 mg/ml, assuming equilibrium isattained in the three-day period. Nevertheless, the 30 mg/ml paclitaxelconcentration is chosen for release studies as it produces the maximumpaclitaxel loading (21-23%), while still being sufficiently below thesaturation concentration for paclitaxel in ethanol (39 mg/ml).

Seven polyurethane coated stents are loaded using a 30 mg/ml paclitaxelsolution, removed and dried as set forth above. Paclitaxel from four ofthe stents is extracted in dichloromethane solvent. The results of thisextraction are presented in Table V below:

TABLE V Paclitaxel content. Paclitaxel Paclitaxel Coating μg Paclitaxelconc. content Wt. per Sample # (mg/ml) (μg) (μg) μg coating 1 30 111.7676 0.17 2 30 50 627 0.08 3 30 45.3 612 0.07 4 30 37.4 602 0.06

The remaining three stents are immersed in a solution of phosphatebuffered saline solution having pH 7.4 at 37° C. Cumulative release as afunction of time is presented in FIG. 8.

Example 9 Release Kinetics of Paclitaxel from Polyurethane-Based BalloonCatheter Coating

Nylon balloons are coated with polyurethane by dipping into a 9 wt %solution of CHRONOFLEX® polyurethane in dimethylacetamide. The balloonsare dried in a vacuum oven overnight at 50° C.

Each polyurethane coated balloon is loaded with paclitaxel either bydipping the coated balloon into a paclitaxel and ethanol solution or bydripping a known volume of a paclitaxel and ethanol solution onto theballoon surface.

In the first instance, a stock saturated solution of paclitaxel inethanol is prepared. Then the polyurethane-coated balloon is inflatedand submerged in the paclitaxel stock solution in a tube. The tube andballoon are well-sealed to prevent solvent evaporation. After remainingin the tube overnight, the ethanol is evaporated from the balloon over asuitable time period, such as about fifteen minutes. Five “dip-coated”balloons are prepared in this fashion.

In the second instance, a stock solution of paclitaxel having aconcentration of 10 mg/ml prepared. Twenty ml of this paclitaxel stocksolution are then pipetted onto an inflated polyurethane-coated balloon,providing a total mass of 200 mg of paclitaxel per balloon. Afterwards,ethanol is evaporated from the balloon over a suitable time period, suchas about fifteen minutes. Five “drip-coated” balloons are prepared inthis fashion.

Two drip-loaded balloons and two dip-loaded balloons are taken and thepaclitaxel extracted in dichloromethane to determine total paclitaxelcontent. The paclitaxel content of the dip-coated balloons is found tobe 1093+/−439 μg, while the drip-coated balloons are found to have215+/−11 μg paclitaxel.

For comparison, nylon balloons are coated with paclitaxel/polyurethaneby dipping the balloons into a dispersion of 14.5 wt % BAHYDROL®polyurethane (made by Bayer) and 2.6 wt % paclitaxel in a mixture of73.6 vol % N-methylpyrrolidinone and 26.4 vol % water. Balloons aredried in a vacuum oven overnight at 50° C. The dried coatings contain15% paclitaxel by weight. Nine balloons are formed. Seven balloons aretested for paclitaxel loading yielding an average of 196+/−44 μgpaclitaxel after extraction in dichloromethane.

The remaining three drip-loaded balloons from above, the remaining threedip-loaded balloons from above, and the remaining two balloons with the15% paclitaxel formulated coating are placed in a solution of phosphatebuffered saline solution having pH 7.4 at 37° C., and cumulativepaclitaxel release is measured as a function of time. The results ofthis study are presented in FIG. 9.

Example 10 Preparation of a Stent-Coated with a PolylacticAcid/Polycaprolactone (PLA/PCL) Copolymer/Paclitaxel Matrix

PLA/PCL copolymer obtained from Birmingham Polymers, Inc., Birmingham,Ala., was dissolved in chloroform. Paclitaxel obtained from Hauser, Inc.was then dissolved in the chloroform to form a solution having a 70/30weight ratio of copolymer/paclitaxel. The solution was then sprayed ontothe surface of a 9 mm long balloon-expandable stainless steel NIR® stentobtained from Medinol, Inc., Tel Aviv, Israel. Substantially all exposedsurfaces of the stent were covered with the solution. The stent was thendried in a vacuum oven at 50° C. for approximately 2 hr. and a matrix ofPLA/PCL copolymer having 200 μg of paclitaxel incorporated therein wasthus formed as a coating on the stent. The paclitaxel component of thematrix comprised approximately 30% by weight of the matrix.

Example 11 In-Vitro Delivery of Paclitaxel to Porcine Coronary Arteries

A stent prepared as set forth in Example 10 was inserted via a ballooncatheter and expanded into contact with a porcine coronary artery. Invitro, the stent delivered 2-3 μg/day of paclitaxel over a period of 28days. In comparison to the same stent having no coating, after 28 days,a 50% reduction in the occurrence of neointimal hyperplasia wasobserved.

Example 12 In-Vitro Delivery of Paclitaxel to Rabbit Iliac

A stent prepared as set forth in Example 10 was inserted via a ballooncatheter and expanded into contact with a rabbit iliac. In vitro, thestent delivered 2-3 μg/day of paclitaxel over a period of 28 days. Incomparison to the same stent having no coating, after 28 days, a 70%reduction in the occurrence of neointimal hyperplasia was observed.

Example 13 In-Vitro Delivery of Paclitaxel to Rabbit Iliac

A stent prepared as set forth in Example 10 was inserted via a ballooncatheter and expanded into contact with a rabbit iliac. In vitro, thestent delivered 2-3 mg/day of paclitaxel over a period of 56 days. Incomparison to the same stent having no coating, after 56 days, a 60%reduction in the occurrence of neointimal hyperplasia was observed.

Comparative Example 14 Coil Stents with Biocompatible PolymericMaterial/TAXOL® Coating

The results presented in Table VI below were obtained by Leon et al.,“TAXOL®-Coated Coronary Stents: Potential to Reduce Proliferation,”European Society of Cardiology, Vienna, Austria 1998. GR-II® coilstents, available from Cook Inc., Bloomington, Ind., were coated with abiocompatible polymeric coating incorporating 175-200 μg of TAXOL® andexhibiting in vitro release kinetics of 0.75 μg/day for the first 30days. The stents were placed in porcine coronary arteries and the effecton neointima formation compared to that seen with control stents wasanalyzed. The results are shown in Table VI below:

TABLE VI TAXOL ®-Coated Stents versus Control TAXOL ®-coated Control (N= 10) Stent (N = 9) Reference Vessel 2.9 ± 0.3 3.0 ± 0.2 Diameter (mm)Stent/Artery 1.1 ± 0.1 1.1 ± 0.1 Diameter Stenosis 51 ± 27  27 ± 27* (%)Neointima Area 669 ± 357  403 ± 197* (μm) *p < 0.05 versus control

In contrast to the results obtained in Example 11 above using the NIR®non-coiled stent in a porcine coronary artery (neointimal hyperplasiareduction of 50%), the results obtained with a coil stent and paclitaxel(placed in a porcine coronary artery) show a neointimal hyperplasiareduction of only 40% calculated as follows: [(669-403)/669]×100=40%.

Comparative Example 15 Comparison of Low-Dose and High DoseTAXOL®-Coated Stents Versus Control

The results of another study by Leon et al., “TAXOL®-Coated Coronary

Stents: Potential to Reduce Proliferation,” European Society ofCardiology, Vienna, Austria 1998 on the effect of coated coil stents onneointima formation using 2 doses of “fast-release” TAXOL® are shown inTable VII below: The results for both “low-dose” and “high-dose”TAXOL®-coated stents are shown in Table VII below:

TABLE VII Low-Dose and High Dose TAXOL ®-Coated Stents versus ControlLow-Dose High-Dose Control TAXOL ® TAXOL ® (N = 12) (N = 10) (N = 11)Reference 2.8 ± 0.2 2.8 ± 0.7 3.0 ± 0.3 Vessel Diameter (mm)Stent/Artery 1.16 ± 0.09 1.15 ± 0.07 1.14 ± 0.05 Diameter 34.8 ± 15.6 19.3 ± 9.45*  15.1 ± 6.61*† Stenosis (%) Neointima 1.52 ± 0.78 1.07 ±0.53  0.93 ± 0.5*† Area (μm) *p < 0.05 versus control †p = notsignificant versus low-dose TAXOL ®

In contrast to the results obtained in Examples 11-13 above using theNIR® non-coiled stent (neointimal hyperplasia reduction of from 50-70%),the above results obtained with a coated coil stent show a neointimalhyperplasia reduction of only 30% and 39%, respectively, calculated asfollows: [(1.52-1.07)/1.52]×100=30% (low-dose TAXOL®) and[(1.52−0.93)/1.52)]×100=39% (high-dose TAXOL®).

Example 16 Preparation of a Vena Cava Filter Coated with a PolylacticAcid/Polycaprolactone (PLA/PCL) Copolymer/Paclitaxel Matrix

A filter for placement in the vena cava for capturing blood clots iscoated with a PLA/PCL copolymer/paclitaxel matrix in the mannersubstantially as set forth in Example 10. The filter is sized andconstructed to be compressed and passed through the vasculature of apatient to be anchored against an inner wall surface of a blood vesselfor capturing blood clots in a blood stream passing therethrough. Thefilter is described in International Application No. WO 96/17634.

Example 17 Preparation of a Vena Cava Filter Coated with a PolylacticAcid/Polycaprolactone (PLA/PCL) Copolymer/Paclitaxel Matrix

A filter for placement in the vena cava for capturing blood clots iscoated with a PLA/PCL copolymer/paclitaxel matrix in the mannersubstantially as set forth in Example 10. The filter is also adapted forplacement in a blood vessel for capturing blood clots in a blood streampassing therethrough. This filter is provided with struts that minimizethe risk of vessel damage if the vessel is compressed asymmetrically.The filter is described in International Application No. WO 96/12448.

Example 18 Preparation of a Vascular Graft Coated with a PolylacticAcid/Polycaprolactone (PLA/PCL) Copolymer/Paclitaxel Matrix

A woven synthetic vascular graft for replacement of a segment a bloodvessel is coated with a PLA/PCL copolymer/paclitaxel matrix in a mannersubstantially as set forth in Example 10. The vascular graft isravel-resistant due to inclusion of a fusible component andself-supporting due to inclusion of a stiffening component. The vasculargraft is described in U.S. Pat. No. 5,509,931.

It is to be appreciated that the parameters described in the aboveexamples are merely illustrative and. that the present invention is notso limited. For example, in each of the examples provided, any suitablepolymer may be used for the polymer coating, any suitable drying timeperiods and temperatures may be used, any suitable organic solvent maybe used, any suitable method for applying the polymer coatings to themedical devices may be used, any suitable method for applying the drugsto the polymer coatings may be used, any suitable water-insolubleanalogue of the disclosed drugs may be used, and any suitable drugloading concentrations may be used.

The present invention provides a previously unknown method and medicaldevice for the localized delivery of substantially water-insolubledrugs. The present invention provides, in one embodiment, apaclitaxel/polymer coated stent which has an extended release rate offrom about 0.2 to about 7 μg per day, preferably in the range of fromabout 0.5 to about 5 μg per lay over an extended period of at leastabout 28 days. In a preferred embodiment of the invention, there isprovided a polymer/paclitaxel coated non-coiled stent which has anextended release rate of paclitaxel and which reduces neointimaformation in injured blood vessels and other body lumens into which itis placed. The extended release rate is effective to prevent, decrease,eliminate, or modify cellular proliferation associated with neointimaformation and/or other proliferative disease or disorder.

Those with skill in the art may recognize various modifications to theembodiments of the invention described and illustrated herein. Suchmodifications are meant to be covered by the spirit and scope of theappended claims.

What is claimed is:
 1. An angioplasty method for delivering paclitaxelto an inner wall of a blood vessel of a patient which comprisesintroducing into the blood vessel of the patient an angioplasty balloonof a medical device having an expandable, percutaneous transluminalangioplasty balloon, the balloon having an outer surface and a driedlayer comprising paclitaxel on the outer surface of the balloon, saidlayer being the only layer on the balloon, and wherein the paclitaxel isnot incorporated within a containment layer; and deploying the balloonto perform angioplasty on the vessel.
 2. An angioplasty method fordelivering paclitaxel to an inner wall of a blood vessel of a patientwhich comprises introducing into the blood vessel of the patient anangioplasty device of a medical device adapted for introduction into thevascular system of a patient, the medical device including theangioplasty device and a dried layer comprising paclitaxel on an outersurface of the angioplasty device, said layer being the only layer onthe angioplasty device, and wherein the paclitaxel is not incorporatedwithin a containment layer; and deploying the angioplasty device toperform angioplasty on the blood vessel.
 3. A method according to claim1, wherein the dried layer consists essentially of paclitaxel.
 4. Amethod according to claim 1, wherein the dried layer consistsessentially of paclitaxel and at least one other bioactive substance. 5.A method according to claim 1, wherein the dried layer is characterizedby being dried onto the outer surface of the balloon by applying asolution including paclitaxel to the outer surface of the balloon andevaporating solvent from the solution.
 6. A method according to claim 2,wherein the dried layer consists essentially of paclitaxel.
 7. A methodaccording to claim 2, wherein the dried layer consists essentially ofpaclitaxel and at least one other bioactive substance.
 8. A methodaccording to claim 2, wherein the dried layer is characterized by beingdried onto the outer surface of the angioplasty device by applying asolution including paclitaxel to the outer surface of the angioplastydevice and evaporating solvent from the solution.